It has long been recognized that prophylactic or therapeutic administration of antibodies (so-called passive immunization) may enhance the ability of the body's immune system to eliminate infectious agents. Such therapeutic antibodies have historically been obtained from human plasma (whence the antibody composition is termed immunoglobulin or gammaglobulin). To obtain these antibodies, pools of blood are collected from immune human donors and the immunoglobulin fraction is extracted and purified. Only a fraction of the immunoglobulin will be specific for a particular antigen. The therapeutic use of immunoglobulin is complicated due to several limitations such as a limited number of donors, expensive manufacturing, risk of infectious contaminants from donors, inevitable batch-to-batch variations as well as complicated administration regimens.
Recombinant monoclonal antibodies have recently provided an alternative to immunoglobulin products. They are, however, only directed against a single target and may therefore not be as effective against targets that are complex or dynamic, such as infectious agents. There are some examples of mixing monoclonal antibodies in order to overcome this problem (e.g. Nowakowski, A. et al. 2002. Proc Natl Acad Sci USA 99, 11346-11350 and U.S. Pat. No. 5,126,130).
Recently a technology for recombinant production of highly specific polyclonal antibodies suitable for prophylactic and therapeutic administration has been developed (WO 2004/061104). The recombinant polyclonal antibody (rpAb) can be purified from a production bioreactor as a single preparation without separate handling, manufacturing, purification, or characterization of the individual members constituting the recombinant polyclonal protein. However, such a production strategy requires a procedure for verifying the identity and demonstrating consistent production of the complex mixture of antibody molecules over time.
Further, a polyclonal antibody produced industrially using recombinant technology will have to be characterized to a certain degree in order to obtain approval as an investigative or therapeutic drug from national and supranational regulatory authorities. Since the recombinant polyclonal antibody approach is a completely new concept, the issue of characterizing a sample comprising multiple different but highly homologous proteins with respect to the relative proportion of the individual proteins in the sample has never been addressed before. Thus, blood-derived immunoglobulin is generally approved based on non-clinical and clinical efficacy data and often historical safety data, as well as crude chemistry, manufacturing, and control (CMC) parameters such as purity, titre of binding, and absence of adventitious agents. Such a simplistic approach is of course not acceptable for recombinantly produced proteins. Hence, for mixtures of a few monoclonal antibodies, the regulatory guidelines state that such a mixture should be subjected to individual characterization of each constituent antibody in the mixture using comprehensive protein chemical characterization techniques coupled with biological assays. However, this is not a technically feasible approach or appropriate for a genuinely polyclonal composition, based on more than 10, 20 or even more different antibodies.